Abemaciclib

CDK4/6 inhibitor with a potent c-Met inhibitory function 1).

CDK4/6 inhibitors are newly FDA-approved agents to treat HER2-positive breast cancer, HER2-negative advanced, and metastatic breast cancers, and preclinical results showed that CDK4/6 inhibitors significantly reduced cell proliferation and tumor growth. However, several studies have suggested that CDK4/6 inhibitor-induced non-genetic changes caused treatment failure, including autophagy activation. Therefore, Hsieh et al. aimed to combine an autophagy inhibitor, MPT0L145, with abemaciclib to improve therapeutic efficiency. The use of abemaciclib effectively inhibited cell proliferation via suppression of RB phosphorylation and induced autophagy activation in glioblastoma cancer cells. MPT0L145 treatment alone not only blocked autophagy activation, but also induced generation of ROS and DNA damage in a concentration-dependent manner. Importantly, MPT0L145 had a comparable penetration ability to TMZ in our blood brain barrier permeability assay. Combined MPT0L145 with abemaciclib significantly reduced cell proliferation, suppressed RB phosphorylation, and increased ROS production. In conclusion, the data suggested that blocking autophagy by MPT0L145 synergistically sensitized Glioblastoma cancer cells to abemaciclib and represents a potential therapeutic strategy for treating Glioblastoma in the future 2).

in vitro analyses of two novel cell models derived from one case with NTRK-fusion revealed that combination therapy with either a MEK (trametinib) or a CDK4/6 (abemaciclib) inhibitor synergistically enhances entrectinib anticancer effects. 3)

The use of abemaciclib, a highly selective CDK4/6 inhibitor, effectively inhibited cell proliferation and reduced the expression of cell-cycle-related and DNA-repair-related gene expression via the suppression of RB phosphorylation, which was determined through RNA-seq and Western blot analyses. Furthermore, abemaciclib effectively induced cell death in vitro. The efficiency of abemaciclib was validated in vivo using subcutaneously implanted ependymoma tissues from patient-derived xenografts (PDXs) in mouse models. Treatment with abemaciclib showed encouraging results in preclinical pediatric ependymoma models and represents a potential therapeutic strategy for treating challenging tumors in children. 4).

5: Das A, Henderson FC Jr, Alshareef M, Porto GBF, Kanginakudru I, Infinger LK, Vandergrift WA 3rd, Lindhorst SM, Varma AK, Patel SJ, Cachia D. MGMT-inhibitor in combination with TGF-βRI inhibitor or CDK 4/6 inhibitor increases temozolomide sensitivity in temozolomide-resistant glioblastoma cells. Clin Transl Oncol. 2021 Mar;23(3):612-619. doi: 10.1007/s12094-020-02456-x. Epub 2020 Jul 25. PMID: 32710211.

6: Tolaney SM, Sahebjam S, Le Rhun E, Bachelot T, Kabos P, Awada A, Yardley D, Chan A, Conte P, Diéras V, Lin NU, Bear M, Chapman SC, Yang Z, Chen Y, Anders CK. A Phase II Study of Abemaciclib in Patients with Brain Metastases Secondary to Hormone Receptor-Positive Breast Cancer. Clin Cancer Res. 2020 Oct 15;26(20):5310-5319. doi: 10.1158/1078-0432.CCR-20-1764. Epub 2020 Jul 21. Erratum in: Clin Cancer Res. 2021 Mar 1;27(5):1582. PMID: 32694159.

7: Cao Y, Li X, Kong S, Shang S, Qi Y. CDK4/6 inhibition suppresses tumour growth and enhances the effect of temozolomide in glioma cells. J Cell Mol Med. 2020 May;24(9):5135-5145. doi: 10.1111/jcmm.15156. Epub 2020 Apr 11. PMID: 32277580; PMCID: PMC7205809.

8: Figura NB, Potluri TK, Mohammadi H, Oliver DE, Arrington JA, Robinson TJ, Etame AB, Tran ND, Liu JK, Soliman H, Forsyth PA, Sahebjam S, Yu HM, Han HS, Ahmed KA. CDK 4/6 inhibitors and stereotactic radiation in the management of hormone receptor positive breast cancer brain metastases. J Neurooncol. 2019 Sep;144(3):583-589. doi: 10.1007/s11060-019-03260-6. Epub 2019 Aug 9. PMID: 31399935.

9: Olmez I, Zhang Y, Manigat L, Benamar M, Brenneman B, Nakano I, Godlewski J, Bronisz A, Lee J, Abbas T, Abounader R, Purow B. Combined c-Met/Trk Inhibition Overcomes Resistance to CDK4/6 Inhibitors in Glioblastoma. Cancer Res. 2018 Aug 1;78(15):4360-4369. doi: 10.1158/0008-5472.CAN-17-3124. Epub 2018 May 29. PMID: 29844123; PMCID: PMC6072607.

1)
Oh JW, Oh YJ, Han S, Her NG, Nam DH. High-Content Analysis-Based Sensitivity Prediction and Novel Therapeutics Screening for c-Met-Addicted Glioblastoma. Cancers (Basel). 2021 Jan 20;13(3):372. doi: 10.3390/cancers13030372. PMID: 33498427; PMCID: PMC7864197.
2)
Hsieh TH, Liang ML, Zheng JH, Lin YC, Yang YC, Vo TH, Liou JP, Yen Y, Chen CH. Combining an Autophagy Inhibitor, MPT0L145, with Abemaciclib Is a New Therapeutic Strategy in Glioblastoma Treatment. Cancers (Basel). 2021 Dec 4;13(23):6117. doi: 10.3390/cancers13236117. PMID: 34885226; PMCID: PMC8656550.
3)
Mayr L, Guntner AS, Madlener S, Schmook MT, Peyrl A, Azizi AA, Dieckmann K, Reisinger D, Stepien NM, Schramm K, Laemmerer A, Jones DTW, Ecker J, Sahm F, Milde T, Pajtler KW, Blattner-Johnson M, Strbac M, Dorfer C, Czech T, Kirchhofer D, Gabler L, Berger W, Haberler C, Müllauer L, Buchberger W, Slavc I, Lötsch- Gojo D, Gojo J. Cerebrospinal Fluid Penetration and Combination Therapy of Entrectinib for Disseminated <i>ROS1/NTRK</i>-Fusion Positive Pediatric High- Grade Glioma. J Pers Med. 2020 Dec 18;10(4):290. doi: 10.3390/jpm10040290. PMID: 33353026; PMCID: PMC7766483.
4)
Liang ML, Chen CH, Liu YR, Huang MH, Lin YC, Wong TT, Lin SE, Chu SS, Ding YH, Hsieh TH. Abemaciclib, A Selective CDK4/6 Inhibitor, Restricts the Growth of Pediatric Ependymomas. Cancers (Basel). 2020 Dec 1;12(12):3597. doi: 10.3390/cancers12123597. PMID: 33271970; PMCID: PMC7760843.